The search for strong analgesics which also possess minimal potential for dependency has been among the highest priority efforts in pharmaceutical research. These research efforts have, to a great extent, involved chemical modifications of the opiate structure and the discovery of novel compounds which possess morphine-like activity.
The discovery of endogenous polypeptide opioids has led workers in the field to consider that these peptides, possessing less rigid liquid structures, might interact with opioid receptors other than those to which the classical rigid structure opiates, such as morphine, bind.
The concept of multiple opioid receptors has been supported by studies with nalorphine and a series of benzomorphans which display unusual pharmacological properties dissimilar from morphine, yet blocked by selective opioid antagonists. [See for example, W. R. Martin, J. Pharmacol. Exp. Ther., 197: 517-532 (1976)].
The existence of multiple types of opioid receptors is of importance because of the possibility of separating desirable analgesic and psychotherapeutic effects of a drug compound from the undesirable abuse potential or habituating effects.
U.S. Pat. No. 4,145,435 describes certain 2-amino-cycloaliphatic amide compounds as analgesics. In particular, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetami de has been reported to possess selective kappa opioid receptor agonist activity, and therefore to possess analgesic activity without attendant dependence liability. [See P. V. Vanvoigtlander et al., J. Pharmacol. Exp. Ther., 224: 7-12 (1983)].
U.S. Pat. No. 4,098,904 discloses certain cis- and trans-N-(2-aminocycloaliphatic)benzamide compounds, for example, N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichlorobenzeneacetamide, which have potent analgesic activity, making them useful for relieving pain in warm-blooded animals.
U.S. Pat. No. 4,212,878 discloses certain N-[[1-amino-4-(substituted)cyclohexyl]methyl]benzeneacetamide compounds, for example, 2-(3,4-dichlorophenyl)-N-[[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl] methyl]acetamide, which also possess analgesic activity with diminished dependence liability.
U.S. Pat. No. 4,360,531 discloses certain N-(2-aminocycloaliphatic)phenylacetamides and benzamides, for example trans-3,4-dichloro-N-methyl[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl ]benzamide as analgesic compounds.
U.S. Pat. No. 4,359,476 discloses certain N-(2-aminocycloaliphatic)phenylacetamides and benzamides, for example, cis- and trans-4-bromo-N-[3-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzamide as analgesic compounds.
U.S. Pat. No. 4,438,130 discloses certain oxaspirocyclohexylbenzeneacetamide and -benzamide compounds, for example 3,4-dichloro-N-methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzenea cetamide, possessing analgesic activity.